Second-Line Treatment Approaches for Metastatic RCC


A brief discussion on current second-line treatment options available to patients with metastatic renal cell carcinoma previously treated with a novel-based regimen.

Sumanta Kumar Pal, MD: You’re starting your patient on lenvatinib and pembrolizumab. In your own words, you’re putting your best foot forward in the front line. What are you going to do for that patient in the second line if they progress? What’s going to be your option there?

Thomas E. Hutson, DO, PharmD: Cabozantinib has become a workhorse for me. Most of what you would choose for the front line would result in me using cabozantinib second. The only situation that I wouldn’t use cabozantinib second would be with people who got cabozantinib-nivolumab first, in which case I would likely be doing lenvatinib-everolimus. Although I’ve been impressed with the tivozanib data.

Sumanta Kumar Pal, MD: What do you think, Dave? I see you nodding there too.

David F. McDermott, MD: I would use cabozantinib off-trial. Trials that build on cabozantinib, like your cabozantinib-atezolizumab study, make a lot of sense. VEGF-HIF trials make a lot of sense right there. We need randomized prospective trials in that group of patients. We have some leads, but your CONTACT-03 is 1 of the few randomized trials. We need more of them.

Sumanta Kumar Pal, MD: This is something I’ve seen a lot in the community, Bob. I’m going to ask you if you’ve seen it in Hackensack, New Jersey, as well. I get a lot of referrals where a patient is on axitinib-pembrolizumab up front. I haven’t had much of a chance to see a lot of cabozantinib-nivolumab or lenvatinib-pembrolizumab in the community. When that patient progresses, I’m seeing them go on to nivolumab-ipilimumab second line, or potentially carry on that PD-1 inhibitor in a combination. Bob, are you seeing that as well? What do you think of that?

Robert S. Alter, MD: We collaborated with Mike Atkins on a GU16-260 study looking at patients getting ipilimumab-nivolumab after failing nivolumab. There were modest response rates, no CRs [complete responses], maybe 12 PRs [partial responses], but they were durable. If you look at the PDIGREE study, not the patients with a CR or with progressive disease, these patients are randomized after ipilimumab-nivolumab to get nivolumab vs nivolumab-cabozantinib. When I have my patients getting ipilimumab-nivolumab and they progress, and I see that they had an initial good response to I/O [immuno-oncology] therapy. I would then add a TKI [tyrosine kinase inhibitor] to the I/O. I would treat them in sequence and still maintain the I/O therapy.

Sometimes we have patients receiving TKI as a single agent for whom, if they show a durable response with good tolerability and they progress, we may just add an I/O to their TKI or change the TKI. There have been enough data recently published in ASCO [American Society of Clinical Oncology], looking at patients receiving I/O who have I/O progressions. This is a community approach that we have. A lot of these patients are being taken care of by physicians who are taking care of a lot of patients with lung cancer and melanoma who routinely use I/O therapy, so they have a high comfort level using I/O therapy with success. This is eventually how, if we’re going to give our patients I/O–I/O or I/O–TKI up front, then we sequence them to a TKI and, by third line, we’re probably going to go back on and add another I/O to that regimen. The sequence is definitely going to be taking off.

Sumanta Kumar Pal, MD: It’s potentially controversial. Tian, what do you think about going from I/O–I/O to TKI–I/O. Do you think that’s a strategy you would use?

Tian Zhang, MD: Sure, I certainly agree with Bob. PDIGREE won’t teach us a lot about that sequence, especially for ipilimumab-nivolumab followed by nivolumab-cabozantinib. It’s a sequence that we’re using in our clinics in patients who are slowly progressing on nivolumab monotherapy maintenance. We’re adding a TKI or changing them to another TKI–I/O combination. These patients can have salvage responses. I even have a few patients in my clinic who have progressed on monotherapies of cabozantinib alone and nivolumab alone. I add them together. Sometimes I don’t know if they’ll respond, and then they have a beautiful synergistic reaction and improvement, and they’re resensitized. These I/O–VEGF combinations in the refractory settings have activity. It’s still hard to tell who will have a durable benefit in that setting.


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